Hepatitis A is a liver disease caused by hepatitis A virus (HAV) infection, which belongs to the Picornaviridae family1. HAV is transmitted through the ingestion of contaminated food and water or even by close physical contact with an infected person2. Once a person gets infected with HAV, lifelong immunity develops3,4. A person with hepatitis A infection may have an asymptomatic state, or may develop symptoms such as fever, nausea or vomiting, abdominal discomfort, jaundice and acute liver failure. Nevertheless, it does not progress to chronic hepatitis2. Unlike hepatitis B and C, hepatitis A is rarely fatal2.
The World Health Organization (WHO) estimates have suggested an increase in the number of acute hepatitis A cases from 117 million in 1990 to 126 million in 2005 with increase in deaths due to hepatitis A from 30,283 (in 1990) to 35,245 (in 2005)5,6. A global seroprevalence study on hepatitis A estimates an intermediate or low, level of endemicity in middle-income countries (MICs) from Asia, Eastern Europe, Latin America and the Middle East6. On the other hand, high-income countries (HICs) generally have low levels of HAV endemicity7.
The severity of hepatitis A infection increases with age, leading to a higher rate of severe disease and death in adults2. In low-income countries (LICs), which usually have a high level of endemicity, nearly all children get infected at an early age and are usually asymptomatic2.
In regions with intermediate endemicity, improved sanitary conditions may lead to the accumulation of adults who have never been infected, hence, have no immunity. These individuals in older age groups, therefore, are at a high risk of symptomatic hepatitis A infection8. Recently, the increasing burden of hepatitis A disease is noted in the regions with intermediate endemicity; thus, the countries in these regions may benefit from new/expanded vaccination programmes8.
HAV vaccination is considered as an effective and safe method to prevent hepatitis A infection2. Worldwide, two types of HAV vaccines (formaldehyde inactivated and live attenuated vaccines) are available2. The WHO recommends HAV vaccination to be integrated into the national immunization schedule for children aged more than one year based on the incidence of hepatitis A, change in endemicity from high to intermediate and considering the cost-effectiveness of the vaccination strategy8.
Economic evaluation (EE) is the comparative analysis of two or more interventions in terms of their costs and consequences9. Three main types of EE methods are cost-effectiveness analysis (CEA), cost-utility analysis (CUA) and cost-benefit analysis (CBA)9. In CEA, cost of each intervention is measured against its effectiveness (e.g. cost per case prevented, cost per life year gained). For CUA, cost incurred in the intervention is measured against the common unit, called quality-adjusted life year (QALY) (e.g. cost per 1 QALY gained). One QALY means one year in full health. For CBA, both cost and consequences of an intervention are expressed in monetary units. Then, the net benefit can be calculated as the difference between cost and consequences9.
To compare the alternative intervention over a long timeframe, modelling techniques have been adopted. Modelling offers several advantages including extrapolation beyond data generated through a trial, synthesizing head-to-head comparisons wherever relevant and linking intermediate endpoint to final outcomes. The most common modelling approaches used in EE studies are decision tree and Markov model10. Unlike decision tree model, Markov model is suitable when timeframe is long, process of disease is complex and events may repeat10.
Evidence generated through EE is important to inform effective healthcare resource allocation. Nevertheless, the capacity to conduct economic studies in many countries is limited11. To date, three systematic reviews on EE of HAV vaccination have been published12-14. The most comprehensive study12 published in 2018 included four studies from MICs and 27 studies from HICs. Another systematic review included nine studies conducted in MICs, which were published till 201213. The other identified 11 EE studies, were published between 1995 and 201014. It should also be noted that methodological characteristics were not fully described in the previous reviews, making it challenging to assess the transferability of the results. Therefore, the aim of this study was to systematically review evidences on cost-effectiveness of hepatitis A vaccination along with epidemiologic parameters and methodological characteristics. Cost-effectiveness evidences were also summarized by the types of population, intervention and income level of the countries.
Material & Methods
This systematic review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines15. The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42018105279).
Search strategy: Relevant studies were identified from PubMed and Scopus database without language restriction from inception to May 31, 2021. For studies other than the English language, help of the language translator from Mahidol University, Bangkok, Thailand was sought. Reference lists of the included studies and previous systematic reviews12-14,16 were also screened. Search terms were constructed based on intervention (I), outcome (O) and study design (S). These were combined using Boolean operators ‘OR’, ‘AND’ for within the same and between the domains, respectively. Both keywords and MeSH terms were used. The full details of search terms and strategies are given in Supplementary Appendix I.
Selection criteria: Duplicate articles were removed by EndNoteX9 software [Camelot UK Bidco Lmtd. (Clarivate analysis), Bangalore, Karnataka, India]. Study selection was performed independently by two authors. Titles and abstracts were screened for potential eligibility. The following criteria were used for screening: (i) full EE comparing HAV vaccine (inactivated or attenuated) to no vaccine or immunoglobulin and, (ii) reported findings in terms of cost per case prevented or incremental cost-effectiveness ratio (ICER) or benefit-to-cost ratio. Studies were excluded if HAV vaccine was investigated in combination with other vaccines, animal studies or studies which reported only clinical effectiveness or disease burden or outbreak investigations or if their fulltext were unavailable. In addition, narrative reviews, systematic reviews, editorial publications, and conference proceedings were also excluded.
Data extraction and quality assessment: Data were extracted independently by two authors using a predesigned data extraction form (Supplementary Appendix II). Any disagreement was resolved by discussion and consensus with a third author. The data extracted included were study and population characteristics, vaccination and comparator details (i.e. vaccine efficacy, vaccination approach), epidemiological parameters (i.e. incidence of HAV), methodological details (i.e. perspective, time horizon, discounting and sensitivity analysis) and EE results.
Risk of bias assessment was performed using the ECOBIAS checklist, which was developed for assessing bias in EE studies17. This 22-item checklist consists of two parts. Part A is related to overall bias, while Part B focusses on model-specific aspects of bias. Results for each item were recorded as ‘yes’, ‘partly addressed’, ‘unclear’, ‘no’ and ‘not applicable’.
Statistical analysis: Descriptive synthesis and narrative summary of study characteristics, participants, interventions, methodology and EE findings were reported according to the income level of the country studied as per the World Bank Report18. Countries were also classified into regions according to the WHO19. According to the World Bank Report 2017, the world’s economies were classified into four income groups based on Gross National Income per capita (current US $) as: LICs (<1005 $), lower-middle-income countries (LMICs) (1006-3955 $), upper-middle income countries (3956-12,235 $) and HICs (>12,235 $)18.
Results
Search results and study characteristics: Of the 1984 studies identified, a total of 43 eligible studies (40 English language and 3 Chinese language) were included in this review. The PRISMA flow diagram for study selection is shown in the Figure with preferred reporting items (Supplementary Appendix III). Selected studies were from 17 different countries: Argentina (2)20,21, Belgium (3)22-24, Brazil (1)25, Canada (1)26 Chile (2)27,28, China (4)29-32, France (1)33, Germany (1)34, Indonesia (1)35, Israel (3)36-38, Jordan (1)39, Mexico (2)40,41, Netherlands (2)42,43, Spain (1)44, Thailand (2)45,46, United Kingdom (1)47, USA (15)25,48-61 and a multi-country study from developed countries62. One study25 was conducted in the USA and Brazil (Table I). Among these, the majority (27/43, 62.8%) were from HICs, followed by MICs (15/43, 34.9%) and LICs (1/43, 2.3%) (Table I).
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Appendix IIIFigure: PRISMA flow diagram for study selection.
Table I: Characteristics of the included studies
As per the WHO regions, the majority of the studies were from America (21/43, 48.8%) followed by Europe (9/43, 20.9%), Eastern Mediterranean (4/43, 9.3%), Western Pacific (4/43, 9.3%) and South-East Asia (3/43, 7.0%). It was not possible to classify a multi-country study from developed countries (1/43, 2.3%). Four studies were published before the licensure of hepatitis A vaccine in 1995 (Table I).
In terms of population, 27 studies were conducted in the general population while 16 were conducted in the specific risk group populations. Of those conducted in the general population, 19, five and three focused on children, adolescents and adults, respectively. Studies conducted among specific risk group population included military personnel (n=4), travellers (n=5), medical students (n=1), healthcare workers (n=3), people with hepatitis B infection (n=1), people with hepatitis C infection (n=2), day-care personnel (n=1), food-handlers (n=1) and homosexuals (n=1) (Table I).
Type of EE studies were CUA (18/43, 41.9%), CEA (14/43, 32.6%), both CUA and CEA (3/43, 7%), CBA (5/43, 11.6%) and CBA and CEA (3/43, 7%). Most studies used Markov model (13/43, 30.2%) followed by Markov model with decision tree (6/43, 14.0%), decision tree (7/43, 16.3%), dynamic model (6/43, 14.0%) and decision tree with dynamic model (2/43, 4.7%) (Table I). Most studies adopted societal (28/43, 65%) and healthcare provider perspective (14/43, 33%). However, nine studies (21%) did not mention the perspective.
Vaccine intervention: The summary of vaccination parameters is reported in Table II. All studies used attenuated hepatitis A vaccine as an intervention. Ten studies disclosed the name of the manufacturer. Vaccine efficacy ranged from 87.3 to 100 per cent (Table II).
Table II: Summary of epidemiological and vaccination parameters used in base case of economic evaluation studies
Epidemiological parameters: As shown in Table II, the incidence of HAV was reported in about half of the studies (22/43), while the seroprevalence was reported in 12 studies. The incidence of HAV varied widely from 1.5 per 100,00033 to 1130 per 100,000 population53. The seroprevalence varied from 0.1-4 per cent44 to 91-94 per cent24. Only 10 studies considered herd immunity in the analysis20,27,28,36,39,40,49,50,54,61.
Risk of bias assessment: The risk of bias assessment for this study is shown in Supplemantary Appendix IV. All included studies had adequate comparators. Only 23.3 per cent (10/43) of the studies adopted a lifetime horizon, while 27.9 per cent (12/43) did not specify a time horizon. In terms of perspective, only 67.4 per cent (29/43) adopted a societal perspective, while about 16.3 per cent (7/43) did not specify the perspective. The discounting rate was not specified in 18.8 per cent of the studies (8/43). Of the 20 studies that disclosed funding sources, 11 were funded by pharmaceutical companies. Eight studies were subjected to risk of bias related to sensitivity analysis. One-way sensitivity analysis was adopted in 72.1 per cent (31/43) of the studies, while probabilistic sensitivity analysis was conducted in only 16.3 per cent (7/43) of the studies. Among CUA studies, 85.7 per cent (18/21) had a partial risk of bias related to quality of life weight. Eleven studies (25.6%) had an unclear risk of double-counting biases. Double-counting occurred when a parameter was counted more than once. It usually occurs in CUA, when consequences of an intervention (i.e. productivity loss/time loss) get incorporated on the cost side (numerator) as well as on the consequences side, i.e. QALY (denominator). All studies in this review had an unclear risk of biases related to internal consistency.
Cost-effectiveness findings: These are summarized in Table III. Summary of cost-effectiveness results by income level of the country, type of population and vaccination strategies is shown in Table IV.
Table III: Summary of economic evaluation studies results
Table IV: Summary of cost-effectiveness results by income level of the country, population and vaccination strategies
For universal vaccination strategy, 70 (7/10), 86.7 (13/15) and 100 per cent (1/1) of the studies conducted respectively, in HICs, MICs and LICs were found to be cost-effective. When examining the types of population, universal vaccination among children was more likely to be cost-effective than the other age groups. About 63 per cent (17/27) of the studies conducted in HICs found that universal vaccination more cost-effective as compared to no vaccination, i.e. 86.7 per cent (13/15) in MICs in contrast to the adult population where, universal vaccination was not found to be cost-effective in both HICs (0/3) and MICs (0/1). Only 50 per cent (1/2) of the studies, comparing screening and vaccination to no vaccination among children in MICs, were found to be cost-effective. On the other hand, screening and vaccination among children in HICs were not cost-effective (0/1).
Hepatitis A vaccine was proven to be cost-effective as compared to no immunization among hepatitis C virus patients, food handlers and the homosexual population in studies conducted in high-income nations that used a targeted vaccination strategy. The results from travellers, healthcare staff and military personnel were mixed. In studies comparing the cost-effectiveness of vaccines vs. no vaccine among travellers, healthcare workers and military people, 40, 33 and 75 per cent were shown to be cost-effective, respectively. In studies comparing screening and vaccination versus no vaccination, 50, 50 and 66.7 per cent were found to be cost-effective among the same categories, respectively (Table IV).
Discussion
The present study revealed that universal hepatitis A vaccination without screening among children, especially in MICs, was more likely to be cost-effective than no vaccine strategy. This finding was consistent with that of earlier studies12,14. This might probably be due to the fact that countries such as Argentina20, Brazil25, Chile28, China30-32, and Indonesia35 have intermediate endemicity. Only half of the studies with data from MICs found that screening and vaccination among children were cost-effective. However, only two such studies were identified in this review. Because of the high seroprevalence of HAV infection among children in MICs, the cost-effectiveness of screening and immunisation was less favoured. In both HICs and MICs, universal hepatitis A vaccination among adults either with or without screening was less likely to be cost-effective. Consistent findings as that was seen in the previous study12, cost-effectiveness evidences among specific risk group populations varied widely depending on the risk of HAV infectivity. It was found that among people with greater risk of acquiring an infection due to a particular occupation or lifestyle, hepatitis A vaccination was found to be economically attractive22,23,43,44,51-53,63,64.
Vaccine considered in the analysis, it should be noted that all studies used inactivated hepatitis A vaccine. However, live-attenuated hepatitis A vaccine has been developed in China since 200765. The vaccine is mainly marketed in China and India65. It was shown to have similar efficacy to that of inactivated vaccine66, but only one dose was required. With the assumption of similar price per dose and similar efficacy, cost-effectiveness evidence would likely favour live-attenuated vaccine.
The present review found that the most common biases identified were related to internal inconsistency in terms of methodological quality. This is similar to other studies67,68, which found that mathematical logic was not evaluated in most of the investigations. Although experts generally recommend using societal perspective, as it is more comprehensive69, a societal perspective was adopted only in 68 per cent of the studies; hence, the direct non-medical cost was not included in the analysis. In addition, we found that only 23 per cent of the studies adopted lifetime horizons. Furthermore, probabilistic sensitivity analysis was rarely conducted.
It should be noted that most of the studies did not use a dynamic model. Furthermore, herd immunity was not taken into account. In fact, a dynamic model was a necessity in deciding on implementing realistic universal vaccination strategies70. However, due to the unavailability of large epidemiological parameters in a local context, complex study design and lack of expertise, the dynamic models were not used widely by researchers. In addition, it should be noted that when herd immunity is not taken into account, cost-effectiveness evidences of vaccine may be underestimated.
Our review found that most included studies had partial bias related to quality of life weight. This was because most of the studies used secondary data with limited information on the methods used to estimate utility weight, as well as characteristics of the sample. In addition, data on utility weights for symptomatic and asymptomatic hepatitis A infection were limited.
It should be noted that cost-effectiveness studies need to be conducted using locally available epidemiological data as such data from other settings have low transferability13. Although the age-specific incidence of hepatitis A infection had a significant impact on cost-effectiveness finding12, we found that many included studies20,21,27,28,31 adopted such data from the US study54,55,71. However, it was suggested that if the hepatitis A incidence data were not available, seroprevalence data of the country could be used to estimate the incidence71,72. In the absence of local data, it is recommended that data from countries with similar endemicity may be used cautiously73. On the other hand, some parameters could be adopted from other countries or other studies. As the natural history of hepatitis A infection is similar across the countries, the probability of symptomatic infection (presented with jaundice) among infected individuals may be transferable from other studies13. Since the efficacy of HAV vaccination was not affected by ethnicity variation, vaccine efficacy data could be adopted from other studies.
In terms of study perspective, most of the studies with societal perspective indicated that HAV vaccination was cost-effective. Studies with societal perspectives, in which HAV vaccination was not found to be cost-effective, were conducted in HICs24,34,42,56,58. For the studies that used both societal perspective and healthcare provider perspective, the results from societal perspective were more favourable towards cost-effectiveness or even cost-saving.
The present systematic review could not identify any EE study on HAV conducted in India. India is considered as a LMIC with wide variation in terms of socio-economic status. Due to rapid improvement in sociodemographic development in India during the past decade, there is evidence of a shift from high to intermediate endemicity, especially in the high-income region. In such region, with the decreasing number of adolescents with prior exposure to HAV, several hepatitis A outbreaks have been reported74-76. According to our review, almost all studies conducted among children in MICs, which were also facing improvement in sociodemographic development, found that HAV vaccination was cost-effective. Therefore, it is likely that HAV vaccination would be cost-effective in India, especially in the regions with reported shift from high to intermediate endemicity. In these regions, policymakers working on HAV vaccination may consider inclusion of HAV vaccination in public insurance schemes.
In summary, our study provides updated cost-effectiveness evidences of hepatitis A vaccination. Based on the existing evidence, we found that universal vaccination among children was more likely to be cost-effective, especially in MICs. Nevertheless, our study had some limitations. First, evidences on LICs and live-attenuated vaccines were limited. Second, as the presented ICERs varied by type of currency, year of valuation and types of outcome, direct comparisons could not be made. Third, most studies had partial biases on both epidemiological parameters and quality of life weights; therefore, further studies that aim to estimate such parameters are warranted to ensure the accuracy of cost-effectiveness evidences. Finally, transferability of the cost-effectiveness findings of hepatitis A vaccine should be made after careful consideration of epidemiological parameters, resource utilization, unit cost data, as well as structure of healthcare delivery system, and country-level income.
Acknowledgment: Authors acknowledge Ms Zhijuan He, Mahidol University, Bangkok, Thailand, for the translation of Chinese papers in the English language.
Financial support & sponsorship: Authors YKG and BSB received financial support through the long term fellowship (R.12011/05/2017-HR) in foreign institute provided by Department of Health Research, Ministry of Health and Family Welfare, Government of India. Authors YKG and BSB received the scholarship from International Decision Support Initiative (www.idsihealth.org), through the training course in Health Technology Assessment’s Master degree at Mahidol University. iDSI received funding support from the Bill and Melinda Gates Foundation, the UK Department for International Development and the Rockefeller Foundation.
Conflicts of Interest: None.
References
1. Hollinger FB, Ticehurst JR Hepatitis A virus Fields BN, Knipe DM, Howley PM Fields virology 3rd ed Philadelphia Lippincott-Raven 1996 735–82.
2. World Health Organization Hepatitis A:2018 Available from:
http://who.int/mediacentre/factsheets/fs328/en/ accessed on October 22, 2019.
3. Koff RS Hepatitis A. Lancet 1998;351:1643–9.
4. Cuthbert JA Hepatitis A:Old and new. Clin Microbiol Rev 2001;14:38–58.
5. World Health Organization.
Evidence based recommendations for use of hepatitis A vaccines in immunization services: Background paper for sage discussions; 2011 Available from:
http://www.who.int/immunization/sage/1_HepABackground_17Oct_final2_nov11.pdf accessed on October 22, 2019.
6. Jacobsen KH, Wiersma ST Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine 2010;28:6653–7.
7. World Health Organization. The global prevalence of hepatitis A virus infection and susceptibility: A
systematic review Available from:
https://apps.who.int/iris/bitstream/handle/10665/70180/ WHO_IVB_10.01_eng.pdf;jsessionid=625E9126160FF3B47B2EE3E93CC60799 ?sequence=1 accessed on October 22, 2019.
8. World Health Organization.
World Health Organization position paper on hepatitis A vaccines – June 2012 Available from:
http://www.who.int/wer/2012/wer8728_29.pdf?ua=1 accessed on October 22, 2019.
9. Drummond MF, Sculpher MJ, Claxton K, Stoddart GL, Torrance GW Methods for the economic evaluation of health care programmes 4th ed Oxford Oxford University Press 2015.
10. Briggs A, Sculpher M, Claxton K Decision modelling for health economic evaluation Oxford Oxford University Press 2006.
11. Oortwijn W, Mathijssen J, Banta D The role of health technology assessment on pharmaceutical reimbursement in selected middle-income countries. Health Policy 2010;95:174–84.
12. Anonychuk AM, Tricco AC, Bauch CT, Pham B, Gilca V, Duval B, et al. Cost-effectiveness analyses of hepatitis A vaccine:A
systematic review to explore the effect of methodological quality on the economic attractiveness of vaccination strategies. Pharmacoeconomics 2008;26:17–32.
13. De Soárez PC, Sartori AM, Santos A, Itria A, Novaes HM, Martelli CM Contributions from the
systematic review of economic evaluations:The case of childhood hepatitis A vaccination in Brazil. Cad Saude Publica 2012;28:211–28.
14. Suwantika AA, Yegenoglu S, Riewpaiboon A, Tu HA, Postma MJ Economic evaluations of hepatitis A vaccination in middle-income countries. Expert Rev Vaccines 2013;12:1479–94.
15. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for
systematic review and meta-analysis protocols (PRISMA-P) 2015:Elaboration and explanation. BMJ 2015;350:g7647.
16. Decimoni TC, Leandro R, Rozman LM, Craig D, Iglesias CP, Novaes HMD, et al.
Systematic review of health economic evaluation studies developed in Brazil from 1980 to 2013. Front Public Health 2018;6:52.
17. Adarkwah CC, van Gils PF, Hiligsmann M, Evers SM Risk of bias in model-based economic evaluations:The ECOBIAS checklist. Expert Rev Pharmacoecon Outcomes Res 2016;16:513–23.
18. The World Bank.
New country classifications by income level: 2017-2018 Available from:
https://blogs.worldbank.org/opendata/new-country-classifications-income-level-2017-2018 accessed on November 25, 2018.
19. World Health Organization.
Health statistics and information systems: WHO; 2018 Available from:
https://www.who.int/healthinfo/global_burden_disease/definition_regions/en/ accessed on December 10, 2019.
20. Lopez E, Debbag R, Coudeville L, Baron-Papillon F, Armoni J The cost-effectiveness of universal vaccination of children against hepatitis A in Argentina:Results of a dynamic health-economic analysis. J Gastroenterol 2007;42:152–60.
21. Ellis A, Rüttimann RW, Jacobs RJ, Meyerhoff AS, Innis BL Cost-effectiveness of childhood hepatitis A vaccination in Argentina:A second dose is warranted. Rev Panam Salud Publica 2007;21:345–56.
22. Tormans G, Van Damme P, Van Doorslaer E Cost-effectiveness analysis of hepatitis A prevention in travellers. Vaccine 1992;10 (Suppl 1) S88–92.
23. Van Doorslaer E, Tormans G, Van Damme P Cost-effectiveness analysis of vaccination against hepatitis A in travellers. J Med Virol 1994;44:463–9.
24. Luyten J, Van de Sande S, de Schrijver K, Van Damme P, Beutels P Cost-effectiveness of hepatitis A vaccination for adults in Belgium. Vaccine 2012;30:6070–80.
25. Ghildayal N Cost-effectiveness of hepatitis A vaccination in a developed and developing country. Int J Health Care Qual Assur 2019;32:1175–99.
26. Ramsay LC, Anyiwe K, Li M, Macdonald L, Coyte PC, Sander B Economic evaluation of a publicly funded hepatitis A travel vaccination program in Ontario, Canada. Vaccine 2019;37:1467–75.
27. Valenzuela MT, Jacobs RJ, Arteaga O, Navarrete MS, Meyerhoff AS, Innis BL Cost-effectiveness of universal childhood hepatitis A vaccination in Chile. Vaccine 2005;23:4110–9.
28. Quezada A, Baron-Papillon F, Coudeville L, Maggi L Universal vaccination of children against hepatitis A in Chile:A cost-effectiveness study. Rev Panam Salud Publica 2008;23:303–12.
29. Li X, Xu Z, Hofman A Epidemiology and cost-effectiveness analysis of hepatitis A vaccination in Liuzhou City. Zhonghua Liu Xing Bing Xue Za Zhi 1998;19:93–6.
30. Chen E, Yao J, Yang J Cost-benefit analysis for hepatitis A vaccine. Zhonghua Liu Xing Bing Xue Za Zhi 1999;20:224–7.
31. Zhuang GH, Pan XJ, Wang XL A cost-effectiveness analysis of universal childhood hepatitis A vaccination in China. Vaccine 2008;26:4608–16.
32. Pan XJ, Feng YM, Zhuang GH Cost-utility analysis on universal childhood hepatitis A vaccination in regions with different anti-HAV prevalence rates of China. Zhonghua Liu Xing Bing Xue Za Zhi 2012;33:862–6.
33. Severo CA, Fagnani F, Lafuma A Cost effectiveness of hepatitis A prevention in France. Pharmacoeconomics 1995;8:46–61.
34. Diel R, Rappenhöner B, Schneider S Cost-effectiveness of hepatitis A immunization of children and adolescents in Germany. HEPAC 2001;2:96–103.
35. Suwantika AA, Beutels P, Postma MJ Cost-effectiveness of hepatitis A vaccination in Indonesia. Hum Vaccin Immunother 2014;10:2342–9.
36. Ginsber GM, Slater PE, Shouval D Cost-benefit analysis of a nationwide infant immunization programme against hepatitis A in an area of intermediate endemicity. J Hepatol 2001;34:92–9.
37. Chodick G, Lerman Y, Peled T, Aloni H, Ashkenazi S Cost-benefit analysis of active vaccination campaigns against hepatitis A among daycare centre personnel in Israel. Pharmacoeconomics 2001;19:281–91.
38. Chodick G, Lerman Y, Wood F, Aloni H, Peled T, Ashkenazi S Cost-utility analysis of hepatitis A prevention among health-care workers in Israel. J Occup Environ Med 2002;44:109–15.
39. Hayajneh WA, Daniels VJ, James CK, Kanıbir MN, Pilsbury M, Marks M, et al. Public health impact and cost effectiveness of routine childhood vaccination for hepatitis a in Jordan:A dynamic model approach. BMC Infect Dis 2018;18:119.
40. Curran D, de Ridder M, Van Effelterre T The impact of assumptions regarding vaccine-induced immunity on the public health and cost-effectiveness of hepatitis A vaccination:Is one dose sufficient?. Hum Vaccin Immunother 2016;12:2765–71.
41. Carlos F, Gómez JA, Anaya P, Romano-Mazzotti L Health economic assessment of universal immunization of toddlers against hepatitis A virus (HAV) in Mexico. Hum Vaccin Immunother 2016;12:52–63.
42. Postma MJ, Bos JM, Beutels P, Schilthuis H, van den Hoek JA Pharmaco-economic evaluation of targeted hepatitis A vaccination for children of ethnic minorities in Amsterdam (The Netherlands). Vaccine 2004;22:1862–7.
43. Buma AH, Beutels P, van Damme P, Tormans G, van Doorslaer E, Leentvaar-Kuijpers A An economic evaluation of hepatitis A vaccination in Dutch military personnel. Mil Med 1998;163:564–7.
44. Arnal JM, Frisas O, Garuz R, Antoñanzas F Cost effectiveness of hepatitis A virus immunisation in Spain. Pharmacoeconomics 1997;12:361–73.
45. Soogarun S, Wiwanitkit V Vaccinating Thai adolescents against hepatitis A:Is it cost-effective?. Southeast Asian J Trop Med Public Health 2002;33 (Suppl 3) 145–8.
46. Teppakdee A, Tangwitoon A, Khemasuwan D, Tangdhanakanond K, Suramaethakul N, Sriratanaban J, et al. Cost-benefit analysis of hepatitis a vaccination in Thailand. Southeast Asian J Trop Med Public Health 2002;33:118–27.
47. Jefferson TO, Behrens RH, Demicheli V Should British soldiers be vaccinated against hepatitis A?An economic analysis. Vaccine 1994;12:1379–83.
48. Arguedas MR, Heudebert GR, Fallon MB, Stinnett AA The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C viral infection in the United States. Am J Gastroenterol 2002;97:721–8.
49. Armstrong GL, Billah K, Rein DB, Hicks KA, Wirth KE, Bell BP The economics of routine childhood hepatitis A immunization in the United States:The impact of herd immunity. Pediatrics 2007;119:e22–9.
50. Chapko MK, Yee HS, Monto A, Dominitz JA Cost-effectiveness of hepatitis A vaccination for individuals with chronic hepatitis C. Vaccine 2010;28:1726–31.
51. Jacobs RJ, Grover SF, Meyerhoff AS, Paivana TA Cost effectiveness of vaccinating food service workers against hepatitis A infection. J Food Prot 2000;63:768–74.
52. Jacobs RJ, Koff RS, Meyerhoff AS The cost-effectiveness of vaccinating chronic hepatitis C patients against hepatitis A. Am J Gastroenterol 2002;97:427–34.
53. Jacobs RJ, Meyerhoff AS Vaccination of sexually active homosexual men against hepatitis A:Analysis of costs and benefits. J Gay Lesbian Med Assoc 1999;3:51–8.
54. Jacobs RJ, Margolis HS, Coleman PJ The cost-effectiveness of adolescent hepatitis A vaccination in states with the highest disease rates. Arch Pediatr Adolesc Med 2000;154:763–70.
55. Jacobs RJ, Greenberg DP, Koff RS, Saab S, Meyerhoff AS Regional variation in the cost effectiveness of childhood hepatitis A immunization. Pediatr Infect Dis J 2003;22:904–14.
56. O'Connor JB, Imperiale TF, Singer ME Cost-effectiveness analysis of hepatitis A vaccination strategies for adults. Hepatology 1999;30:1077–81.
57. Rein DB, Hicks KA, Wirth KE, Billah K, Finelli L, Fiore AE, et al. Cost-effectiveness of routine childhood vaccination for hepatitis A in the United States. Pediatrics 2007;119:e12–21.
58. Smith S, Weber S, Wiblin T, Nettleman M Cost-effectiveness of hepatitis A vaccination in healthcare workers. Infect Control Hosp Epidemiol 1997;18:688–91.
59. Wilson KJ, Brown HS, Patel U, Tucker D, Becker K Cost-effectiveness of a comprehensive immunization program serving high-risk, uninsured adults. Prev Med 2020;130:105860.
60. Hankin-Wei A, Rein DB, Hernandez-Romieu A, Kennedy MJ, Bulkow L, Rosenberg E, et al. Cost-effectiveness analysis of catch-up hepatitis A vaccination among unvaccinated/partially-vaccinated children. Vaccine 2016;34:4243–9.
61. Dhankhar P, Nwankwo C, Pillsbury M, Lauschke A, Goveia MG, Acosta CJ, et al. Public health impact and cost-effectiveness of hepatitis A Vaccination in the United States:A Disease Transmission Dynamic Modeling Approach. Value Health 2015;18:358–67.
62. Das A An economic analysis of different strategies of immunization against hepatitis A virus in developed countries. Hepatology 1999;29:548–52.
63. Jacobs RJ, Saab S, Meyerhoff AS The cost effectiveness of hepatitis immunization for US college students. J Am Coll Health 2003;51:227–36.
64. Jacobs RJ, Rosenthal P, Meyerhoff AS Cost effectiveness of hepatitis A/B versus hepatitis B vaccination for US prison inmates. Vaccine 2004;22:1241–8.
65. World Health Organization Live attenuated hepatitis A vaccine Available from:
https://www.who.int/vaccine_safety/committee/topics/hepatitisa/Jun_2010/en/ accessed on April 27, 2019.
66. Irving GJ, Holden J, Yang R, Pope D Hepatitis A immunisation in persons not previously exposed to hepatitis A. Cochrane Database Syst Rev 2019;12:CD009051.
67. Vaidya A, Joore MA, ten Cate-Hoek AJ, Kleinegris MC, ten Cate H, Severens JL A
systematic review of model-based economic evaluations of diagnostic and therapeutic strategies for lower extremity artery disease. Thromb Haemost 2014;111:19–28.
68. van Haalen HG, Severens JL, Tran-Duy A, Boonen A How to select the right cost-effectiveness model?:A
systematic review and stepwise approach for selecting a transferable health economic evaluation model for rheumatoid arthritis. Pharmacoeconomics 2014;32:429–42.
69. Pignone M, Saha S, Hoerger T, Lohr KN, Teutsch S, Mandelblatt J Challenges in systematic reviews of economic analyses. Ann Intern Med 2005;142:1073–9.
70. Beutels P, Edmunds WJ, Antoñanzas F, De Wit GA, Evans D, Feilden R, et al. Economic evaluation of vaccination programmes:A consensus statement focusing on viral hepatitis. Pharmacoeconomics 2002;20:1–7.
71. Armstrong GL, Bell BP Hepatitis A virus infections in the United States:Model-based estimates and implications for childhood immunization. Pediatrics 2002;109:839–45.
72. Muench H Catalytic models in epidemiology Cambridge Harvard University Press 1959.
73. Barbieri M, Drummond M, Rutten F, Cook J, Glick HA, Lis J, et al. What do international pharmacoeconomic guidelines say about economic data transferability?. Value Health 2010;13:1028–37.
74. Rakesh PS, Sreelakshmi MK 84 outbreaks of hepatitis A in last five years in Kerala state-are we resigning to fate?
Natl J Res Community Med 2017;6:267–70.
75. Mathur P, Arora NK Epidemiological transition of hepatitis A in India:Issues for vaccination in developing countries. Indian J Med Res 2008;128:699–704.
76. Gurav YK, Retheesh Babu G, Vinu KP, Lole KS Suspected spread of hepatitis A virus from a restaurant among adults in rural area of the Kerala state, India. Epidemiol Infect 2019;147:e210.
